Field of the invention

The present invention relates to an oral dosage form comprising an estrogenic compound and process of preparation thereof. Particularly, the present invention relates to an oral dosage form comprising an estrogenic and progestogenic compound. More particularly, the present invention relates to process for the preparation of oral dosage form comprising ethinyl estradiol and desogestrel.

Background of the invention

Oral contraceptives including progestogen and estrogen components, and their combinations are used for decades. Ethinyl estradiol is a synthetic estrogenic compound, chemically known as 19-nor-17a-pregna 1,3,5(10)-triene-20-yne-3,17-diol.

Ethinylestradiol is currently marketed in the United States in combination with desogestrel (Kariva®, Desogen®, Cyclessa®, Mircette®); with drospirenone (Yasmin® and Yaz®); with levonorgestrel (Seasonique®, Loseasonique®, Seasonale®, Lybrel®); with norethindrone (Norinyl®, Ovcon-35®, Ovcon-50®); with norethindrone acetate (Femhrt®) and with norgestimate (Ortho cyclen®, Ortho Tricyclen®, Ortho Tricyclen Lo®).

The pharmaceutical industry employs various methods for compounding pharmaceutical agents in tablet formulations. In particular granulation is one of the most prevalent methods.

Granulation is a process whereby granules are formed from a bulk drug substance with or without excipients to improve the properties of the bulk drug or formulation. Granules are preparations consisting of solid, dry agglomerates of powder particles sufficiently robust to withstand handling.

Wet granulation is distinguished from dry granulation in that a granulating liquid, such as water, organic liquids or mixtures thereof, are used in wet granulation to produce granules. The advantages of wet granulation include improvement of the cohesiveness and compatibility of powders, increase in density and good distribution providing uniform content of micronized or finely milled low-dosage drugs, reduction of dust and airborne contamination, and prevention of segregation of components.

There are several patents/patent publications, which disclose pharmaceutical compositions and process for the preparation of said compositions of estrogenic and progestogenic compound.

US 4,378,356 discloses multi-phase combination-type sequential preparation for oral contraception consisting of 20-22 tablets each containing a gestagen and an oestrogen.

US 4,544,554 discloses triphasic contraceptive composition comprising a combination of an estrogen and a progestogen.

US RE 35,724 discloses a method of contraception composition comprising about 0.01 to about 0.04 mg of ethinylestradiol and progestin.

US 5,262,408 discloses multiphasic combination contraceptive kit comprising progestogen at a dosage equivalent in progestogenic activity to 75-100 ug desogestrel, estrogen at a dosage equivalent in estrogenic activity to 25 ug ethinyl estradiol and a pharmaceutically acceptable carrier.

US 5,382,434 discloses a dosage unit consisting essentially of 1 to 100 parts by weight of steroidal agent uniformly distributed throughout 2000 to 20,000 parts by weight of excipient using dry mixing process.

US 5,395,627 discloses that steroids such as desogestrel transfer from tablets into the surrounding local environment. If the transfer of the steroid from the tablet cannot be prevented, the quantity of steroid contained within the dosage unit may drop below stated levels within a relatively short period of time. To prevent transfer of the compound out of the dosage unit, US '627 discloses a granule for tabletting comprising lactose, polyvinylpyrolidone, disintegrating agent and film coating said carrier with desogestrel and stearic acid.

US 5,527,543 discloses a process for preparing granules comprising dissolving one or more steroids in a lubricant in a sufficient amount of an organic solvent to form a solution; mixing the solution with a carrier comprising diluent and binder thus forming a mixture of solution and carrier; and removing the organic solvent from the mixture.

US 5,478,571 discloses a method for the preparation of a composition comprising solubilizing drug in an organic solvent, mixing the drug solution with inert carrier material removing the solvent from drug carrier blend and adding water.

US 5,662,936 discloses a sugar-coated dosage unit comprising desogestrel and ethinyl estradiol to prevent moisture to enter the tablet or granule and to prevent the transfer of a steroid, such as desogestrel, allylestrenol, ethylestrenol, or lynestrenol from the tablet or granule to the environment.

US 5,709,881 discloses a pharmaceutical composition free from organic solvents in a solid matrix for oral administration comprising desogestrel mixed or dissolved in a solid selected from a lubricant, a waxy substance that is not a lubricant and mixtures thereof.

US 5,759,576 discloses a sugar coating composition for application to a compressed medicinal tablet comprising a sugar, a loading dose of a hormonal steroid and a steroid release rate controlling amount of microcrystalline cellulose.

US 5,916,593 discloses mixing desogestrel with excipients and water and granulating the said mixture.

US 5,928,668 discloses a composition comprising one or more low dosage medicaments and an excipient selected from the group consisting of mannitol, maltodextrin, corn syrup solid and mixtures thereof and, optionally, one or more excipient, disintegrating agent, or lubricant

US 5,976,570 discloses a process for making dosage units comprising one or more low dosage medicinal agent comprising the steps of: preparing an aqueous medium comprising surfactant and granulating one or more low dose medicinal agents in said aqueous medium to form granulation.

US 6,063,403 discloses a method of producing compressed dry-granulation tablets of desogestrel by compressing material comprising desogestrel at elevated pressure to produce compressed material; crushing the compressed material to produce particles; and processing the particles into tablets.

US 6,187,339 discloses a composition comprising at least one solvent or dispersant, a low dosage active ingredient, and a water insoluble non-cross-linked polymeric excipient having particle size distribution wherein at least 50% of the particles by volume have a diameter of from 150u to 200 u,

US 6,761,907 discloses a composition comprising a steroid and as an end-layer, a seal coat that prevents transfer of the steroid out of the pharmaceutical composition comprising a resin or a copolymer of dimethylaminoethyl methacrylate and methacrylic acid ester.

US 2005/0181040 discloses a a method of producing pharmaceutical dosage units by dissolving the progestagenic compound in an organic solvent to form a solution; mixing the resulting solution with a carrier; granulating and drying the resulting mixture; mixing with excipients and turning the resulting mixture into dosage units.

The afore-mentioned prior art references disclose various methods of preparation of dosage form comprising low dose active substances such as steroids employing direct compression, dry granulation or granulating excipients using drug solution in organic solvents. However, the inventors of the present invention have endeavored to develop a process wherein the loss of active substance from the dosage form is minimized by blending and compressing the granules comprising the active substances and the granules of excipients into solid dosage form, and wherein said granules are prepared by wet granulation process, thereby achieving good content uniformity. Further, the compositions of the present invention are highly stable.

Objective of the invention

An objective of the present invention is to provide stable dosage form of ethinyl estradiol.

Another objective of the present invention is to provide stable dosage form of ethinyl estradiol and progestogen.

Another objective of the present invention is to provide a process for preparation of stable dosage form of ethinyl estradiol and progestogen.

Another objective of the present invention is to provide a process for preparation of stable dosage form of ethinyl estradiol and desogestrel.

Another objective of the present invention is to provide a process for the preparation of stable dosage form of ethinyl estradiol and progestogen, wherein the said process is a wet granulation process.

Still another objective of the present invention is to provide a process for the preparation of stable dosage form of ethinyl estradiol and desogestrel, wherein the said process is a wet granulation process.

Summary of the invention

The present invention provides a stable dosage form comprising ethinyl estradiol.

The present invention provides a process for the preparation of stable oral dosage form comprising ethinyl estradiol.

The present invention also provides a process for the preparation of stable oral dosage form comprising ethinyl estradiol and one or more progestogens.

The present invention provides a stable dosage form comprising ethinyl estradiol and desogestrel.

The present invention also provides a process for the preparation of stable oral dosage form comprising ethinyl estradiol, wherein ethinyl estradiol is not in intimate contact with a binder.

In an embodiment, the present invention provides a process for the preparation of stable oral dosage form comprising ethinyl estradiol, wherein ethinyl estradiol is not in intimate contact with a binder, such as polyvinyl pyrrolidone (povidone).

The present invention also provides a process for the preparation of oral dosage form comprising ethinyl estradiol and progestogen comprising the steps of:

(i) granulating one or more excipients using a solution/dispersion comprising progestogen and ethinyl estradiol,

(ii) optionally granulating one or more excipients using a solvent with an optional binder,

(iii) blending the granules of step (i) and optionally step (ii) with one or more excipients and (iv) formulating the blend obtained in step (iii) into solid dosage form.

Detailed description of the invention

The present invention provides stable dosage form comprising ethinyl estradiol and process of preparation thereof.

In an aspect, the present invention provides a process for the preparation of stable oral dosage form comprising ethinyl estradiol.

In an aspect, the present invention provides a process for the preparation of stable oral dosage form comprising ethinyl estradiol and one or more progestogens.

In an embodiment, the progestogen is selected from a group comprising desogestrel, norgestrel, levonorgestrel, norethindrone, norgestimate, drosperinone, and the like, or mixtures thereof.

In an aspect, the present invention provides a stable dosage form comprising ethinyl estradiol and desogestrel.

The present invention also provides a process for the preparation of stable oral dosage form comprising ethinyl estradiol, wherein ethinyl estradiol is not in intimate contact with a binder.

In an embodiment, the present invention provides a process for the preparation of stable oral dosage form comprising ethinyl estradiol, wherein ethinyl estradiol is not in intimate contact with a binder, such as polyvinyl pyrrolidone (povidone).

In another embodiment, the present invention also provides a process for the preparation of oral dosage form comprising ethinyl estradiol and progestogen comprising the steps of:

(i) granulating one or more excipients using a solution/dispersion comprising progestogen and ethinyl estradiol,

(ii) optionally granulating one or more excipients using a solvent with an optional binder,

(iii) blending the granules of step (i) and optionally step (ii) with one or more excipients and (iv) formulating the blend obtained in step (iii) into solid dosage form.

In another embodiment, one or more pharmaceutically acceptable excipients are selected from but not limited to a group comprising diluent, binder, disintegrant, surfactant, antioxidants, glidant and lubricant.

In another embodiment, solution/dispersion comprising progestogen and ethinyl estradiol further comprises one or more pharmaceutically acceptable excipients selected from a group comprising antioxidants, surfactants, glidants and lubricants.

In yet another embodiment, the amount of progestogen used may be in the range from about 0.005% to about 0.5% and the amount of ethinyl estradiol used may be in the range from about 0.001% to about 0.5%.

In yet another embodiment, the amount of progestogen used may be in the range from about 0.025% to about 0.15% and the amount of ethinyl estradiol used may be in the range from about 0.01% to about 0.05%.

Various literatures disclose that ethinyl estradiol is being affected by oxidative substance like povidone which may increase the oxidative impurity of ethinyl estradiol. Solubilization of ethinyl estradiol along with povidone in organic solution for granulation purpose might increase the impurity profile of product as rate of reaction is too high at molecular level. To reduce the level of impurities separately granulating lactose with povidone/ extra-granular addition of povidone reduces the risk of generation of undesirable levels of chemical impurities/degradants of ethinyl estradiol as the solid-solid interaction is much less compared to the liquid-liquid interaction.

Suitable diluents used according to the present invention are selected from sugars such as lactose, sucrose, dextrose; sugar alcohols such as mannitol, sorbitol, xylitol, lactitol; starch, corn starch, modified starches, pregelatinized starch, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and the like or combinations thereof. The amount of diluent may range from about 10-95%, preferably 30-85% by weight of the dosage form.

Suitable binders used according to the present invention are selected from the group comprising pregelatinized starch, polyvinyl pyrrolidone, copovidone, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose; starch and its derivatives; hydrocolloids; methacrylic acid copolymers and the like or combination thereof. The amount of binder may range from about 1 -20%, preferably 2-10% by weight of the dosage form.

Suitable disintegrants used according to the present invention are selected from low-substituted hydroxypropyl cellulose; cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose; sodium starch glycolate; pregelatinized starch and the like or combinations thereof. The amount of disintegrant may range from about 1-20%, preferably 2-10% by weight of the dosage form.

Suitable lubricants used according to the present invention are selected from calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate and the like or combinations thereof. The amount of lubricant may range from about 0.1-5%, preferably 1-3% by weight of the dosage form.

Suitable glidants of the present invention include calcium silicate, magnesium carbonate, magnesium oxide, magnesium silicate, talc, colloidal silicon dioxide, starch and the like. The glidant may be used in the range of 0.1-5%, preferably 1-3% by weight of the dosage form.

Antioxidants prevent the oxidative degradation of substance. Exemplary anti-oxidants include, but not limited to, ascorbic acid and its salts and derivatives, vitamin E, vitamin E acetate, tocopherols and their derivatives, citric acid, gallic acid ester, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), di-tert-butylphenol, tertiary butylhydroquinone and the like or combinations thereof. The antioxidant may be used in the range of 0.001-5% by weight of the dosage form.

Suitable surfactants used according to the present invention are selected from sodium lauryl sulphate, polyethylene-propylene glycol copolymer (poloxamer), cremophor-40, polyoxyethylene stearates (Macrogol-stearate), polysorbates, propylene glycol, and the like or mixtures thereof.

In an embodiment, the present invention also provides a process for the preparation of oral dosage form comprising ethinyl estradiol and desogestrel comprising the steps of:

(i) granulating one or more excipients using a solution/dispersion comprising desogestrel and ethinyl estradiol,

(ii) optionally granulating one or more excipients using a solvent with an optional binder,

(iii) blending the granules of step (i) and optionally step (ii) with one or more excipients and (iv) formulating the blend obtained in step (iii) into solid dosage form.

In another embodiment, the present invention provides a process for the preparation of oral dosage form comprising ethinyl estradiol and desogestrel comprising the steps of:

(i) granulating about 50-85% of diluent using a solution/dispersion comprising desogestrel, ethinyl estradiol, about 0.5-1.5% of antioxidant and about 1-3% of lubricant,

(ii) optionally granulating about 50-85% of diluent using a solvent with an optional binder,

(iii) blending the granules of step (i) and optionally step (ii) with about 5-20% of diluent, about 5-20% of binder, about 0-5% of disintegrant, about 1-3% of glidant, about 1-3% of lubricant, and (iv) formulating the blend obtained in step (iii) into solid dosage form.

In another preferred embodiment, the present invention also provides a process for the preparation of oral dosage form comprising ethinyl estradiol and desogestrel comprising the steps of:

(i) granulating about 50-85% of diluent selected from lactose, microcrystalline cellulose using a solution/dispersion comprising desogestrel, ethinyl estradiol, about 0.5-1.5% of antioxidant selected from Vitamin E, butylated hydroxy toluene and 1-3% of lubricant selected from stearic acid, magnesium stearate;

(ii) optionally granulating about 50-85% of diluent selected from lactose, microcrystalline cellulose using a solvent with an optional binder selected from povidone, pregelatinised starch,

(iii) blending the granules of step (i) and optionally step (ii) with about 5-20% of diluent selected from lactose, microcrystalline cellulose, about 5-20% of binder selected from povidone, pregelatinised starch, about 0-5% of disintegrant, about 1-3% of glidant selected from colloidal silicon dioxide, talc, about 1-3% of lubricant selected from stearic acid, magnesium stearate, and (iv) formulating the blend obtained in step (iii) into solid dosage form.

In an embodiment of the present invention, the solvents used for granulation may be selected from isopropyl alcohol, methanol, ethanol, water, acetone, methylene chloride and the like or mixtures thereof.

In another embodiment of the present invention, the solid dosage forms include tablets and capsules. The tablets may be uncoated or optionally coated.

In yet another embodiment of the present invention, film coating composition comprises a solution / suspension of film coating polymers and one or more excipients such as lactose, titanium dioxide, solubilizing agent and antisticking agent.

Suitable film coating polymers used according to the present invention are selected from ethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose and the like or mixtures thereof.

Suitable anti-sticking agents used according to the present invention are selected from talc, magnesium stearate and the like or a mixture thereof.

Yet another objective of the present invention is to provide stable dosage form compositions comprising ethinyl estradiol and desogestrel such that the dosage forms exhibits substantially similar in vivo parameters like Cmax> Tmax and AUC, and in vitro parameters like dissolution, as compared to the reference product.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example-1

The processing steps involved in manufacturing progestogen and Ethinyl estradiol tablets are as follows: Granules -1

(a) Lactose monohydrate was sifted and blended,

(b) Progestogen, ethinyl estradiol, vitamin E and stearic acid were dissolved in methylene chloride and methanol,

(c) The blend of step (a) was granulated using the solution of step (b) and the wet mass was dried, milled and sifted,

Granules -2

(d) Lactose monohydrate was sifted and blended and granulated with a solution of povidone in methanol,

(e) Granules of step (d) were dried, milled and sifted, Compression

(f) The granules of step (c) and the granules of step (e) were blended with lactose monohydrate, pregelatinised starch, and colloidal silicon dioxide,

(g) The blend of step (f) was lubricated with stearic acid and was compressed into tablets,

(h) The compressed tablets obtained in step (g) were coated with Opadry® coating.

ExampIe-2

The processing steps involved in manufacturing desogestrel and Ethinyl estradiol tablets are as follows: Granules -1

(a) Lactose monohydrate was sifted and blended,

(b) Desogestrel, ethinyl estradiol, vitamin E and stearic acid were dissolved in methylene chloride and methanol,

(c) The blend of step (a) was granulated using the solution of step (b) and the wet mass was dried, milled and sifted,

Granules -2

(d) Lactose monohydrate was sifted and blended, and granulated with a solution of povidone in methanol,

(e) Granules of step (d) were dried, milled and sifted, Compression

(f) The granules of step (c) and the granules of step (e) were blended with lactose monohydrate, pregelatinised starch and colloidal silicon dioxide,

(g) The blend of step (f) was lubricated with stearic acid and was compressed into tablets,

(h) The compressed tablets obtained in step (g) were coated with Opadry® coating.

Example-3

The processing steps involved in manufacturing desogestrel and Ethinyl estradiol tablets are as follows:

(a) Lactose monohydrate and part of stearic acid was sifted and blended,

(b) Desogestrel, ethinyl estradiol, vitamin E and remaining part of stearic acid were dissolved in methylene chloride and methanol,

(c) The blend of step (a) was granulated using the solution of step (b) and the wet mass was dried, milled and sifted,

(d) The granules of step (c) were blended with extragranular lactose monohydrate, povidone, pregelatinised starch and colloidal silicon dioxide,

(e) The blend of step (d) was lubricated with stearic acid and then compressed into tablets.

Claims:

1. A process for the preparation of stable oral dosage form comprising ethinyl estradiol, characterized in that the undesirable levels of chemical impurities/degradants of ethinyl estradiol are not formed during the preparation of said dosage form.

2. A process for the preparation of stable oral dosage form according to claim 1, comprising ethinyl estradiol and one or more progestogens.

3. A process for the preparation of stable oral dosage form according to claim 1 or 2, wherein ethinyl estradiol is not in intimate contact with a binder.

4. A process according to claim 3, wherein the binder is polyvinyl pyrrolidone.

5. A process for the preparation of oral dosage form comprising ethinyl estradiol and progestogen according to any of the preceding claims 1-4, comprising the steps of:

(i) granulating one or more excipients using a solution/dispersion comprising progestogen and ethinyl estradiol,

(ii) optionally granulating one or more excipients using a solvent with an optional binder,

(iii) blending the granules of step (i) and optionally step (ii) with one or more excipients and

(iv) formulating the blend obtained in step (iii) into solid dosage form.

6. The dosage form according to preceding claims 2-5, wherein a progestogen is selected from a group comprising desogestrel, norgestrel, levonorgestrel, norethindrone, norgestimate and drosperinone.

7. The dosage form according to preceding claims 1-6, comprising one or more pharmaceutically acceptable excipients selected from a group comprising diluent, binder, disintegrant, surfactant, antioxidant, glidant and lubricant.

8. A process for the preparation of oral dosage form comprising ethinyl estradiol and desogestrel according to any of the preceding claims 2-7 comprising the steps of:

(i) granulating one or more excipients using a solution/dispersion comprising desogestrel and ethinyl estradiol,

(ii) optionally granulating one or more excipients using a solvent with an optional binder,

(iii) blending the granules of step (i) and optionally step (ii) with one or more excipients and,

(iv) formulating the blend obtained in step (iii) into solid dosage form.

9. A process for the preparation of oral dosage form comprising ethinyl estradiol and desogestrel according to any of the preceding claims 2-7 comprising the steps of:

(i) granulating about 50-85% of diluent using a solution/dispersion comprising desogestrel, ethinyl estradiol, about 0.5-1.5% of antioxidant and 1-3% of lubricant,

(ii) optionally granulating about 50-85% of diluent using a solvent with an optional binder,

(iii) blending the granules of step (i) and optionally step (ii) with about 5-20% of diluent, about 5-20% of binder, about 0-5% of disintegrant, about 1-3% of glidant, about 1-3% of lubricant and,

(iv) formulating the blend obtained in step (iii) into solid dosage form.

10. A process for the preparation of oral dosage form comprising ethinyl estradiol and desogestrel according to any of the preceding claims 2-7 comprising the steps of:

(i) granulating about 50-85% of diluent selected from lactose, microcrystalline cellulose using a solution/dispersion comprising desogestrel, ethinyl estradiol, about 0.5-1.5% of antioxidant selected from Vitamin E, butylated hydroxy toluene and 1-3% of lubricant selected from stearic acid, magnesium stearate;

(ii) optionally granulating about 50-85% of diluent selected from lactose, microcrystalline cellulose using a solvent with an optional binder selected from povidone, pregelatinised starch,

(iii) blending the granules of step (i) and optionally step (ii) with about 5-20% of diluent selected from lactose, microcrystalline cellulose, about 5-20% of binder selected from povidone, pregelatinised starch, about 0-5% of disintegrant, about 1-3% of glidant selected from colloidal silicon dioxide, talc, about 1-3% of lubricant selected from stearic acid, magnesium stearate, and (iv) formulating the blend obtained in step (iii) into solid dosage form.